Prolonged action drug formulation

ABSTRACT

The time during which a drug is pharmacologically active is prolonged by coating the drug with at least one chemical derivative of the drug having minor relative pharmacological activity.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of my application Ser. No. 06/343,663filed Jan. 28, 1982, now U.S. Pat. No. 4,461,770 which, in turn, is acontinuation-in-part of my application Ser. No. 142,279, filed Apr. 22,1980.

FIELD OF THE INVENTION

The field of art to which the invention pertains includes the field ofsustained and controlled release drug delivery systems and formulations.

BACKGROUND AND SUMMARY OF THE INVENTION

Medical science has long recognized the desirability of prolonging thetime during which a drug is pharmacologically active. A significantadvantage is to decrease the frequency with which the patient has totake the drug or be given the drug. This is particularly important whenpatient compliance problems are encountered such as with psychiatricpatients or with the senile. Extending the pharmacological activity ofthe drug can have significant therapeutic benefits, for example, bypermitting a patient to sleep undisturbed throughout the night. Perhapsmost significantly, the patient is exposed to less total active drugduring any given period of time, minimizing or eliminating local andsystemic side effects. Prolonged action drug formulations have utilityin veterinary medicine, particularly in the treatment of free-ranginganimals.

A variety of methods have been devised in an attempt to increase drugrelease time, including oral, parenteral and topical applicationtechniques. For example, drugs have been encapsulated in polymer or inslowly-dissolving coating material, or have been dispersed in aninsoluble or slowly-dissolving matrix. Prolonged activity formulationsdesigned for subcutaneous and intramuscular injection have been preparedby using polymers to complex or absorb the drug molecules in solution.Other techniques include suspension of polymer particles into which thedrug is dispersed, suspension of microcapsules of the drug, use ofsolutions or suspensions of the drug in oil, or emulsions with oil, andimplanting various slow release devices or pellets. These and othermethods for providing prolonged activity are described in "Sustained andControlled Release Drug Delivery Systems" by J. R. Robinson, MarcelDekker, Inc., New York, 1978 (Volume 6 of "Drugs and the PharmaceuticalSciences" Series, edited by J. Swarbrick).

Most pertinent to the present development are the methods described byAnthony A. Sinkula in Chapter 6 of the foregoing text relating to thechemical approach to sustained drug delivery; that Chapter 6 isincorporated herein by reference. Such methods are based uponlocalization of the drug in a biological depot or site within theorganism with slow release to provide the active form of the drug overan extended length of time. The author describes preparation of chemicalderivatives of a wide variety of drugs to increase the sustained releaseproperty of the drug molecule. In many cases, the parent molecule isregenerated in vivo by a hydrolytic mechanism. While the chemicalapproach would seem to offer hope for a wide variety of custom tailoredprolonged action drugs, when the derivative is formulated so as toprovide a significant level of drug delivery, there are a number ofdrawbacks pointed out by Sinkula. For example, the resulting changes inthe physiochemical properties of the modified drug may well producepharmacological and biochemical changes different from those found inthe parent drug molecule. The predictability of these changes isdifficult to assess, and frequently it is not possible to alter only oneproperty of the drug. It will be appreciated that the foregoing problemsarise as a result of attempting to provide a modified drug at aconcentration level having substantial pharmacological activity.

The present invention provides a prolonged action drug formulation inwhich chemical derivatives of the desired drug are utilized, forexample, as a matrix or coating within which the desired drug islocated. However, in the present invention as compared to the prior useof drug derivatives, the concentration of the drug derivatives are suchas to provide only minor pharmacological activity. Rather than simplyrelying upon regeneration of the drug by decomposition of a derivative,according to the present invention the derivatives retain their identityfor an extended period of time in combination with desired quantities ofthe drug itself, serving by such combination to impede the release ofthe drug. Succinctly, the desired drug is dispersed in at least onesuitable chemical derivative which has a reduced aqueous solubility andreduced dissolution rate.

It will be appreciated that there are several advantages to the presentinvention. In particular, since the pharmacological activity of themodified drug is minor relative to the activity of the drug with whichit is in combination, there is little likelihood of pharmacological andbiochemical changes in the derivative; there is thus a cost savingsthrough reduced toxicity testing and dosage development time. Therelationship between drug release and concentration in the combinationcan be readily determined and customized for any particular applicationby simple changes in concentration and/or the manner by which the drugand derivative are placed in combination. For example, it may bedesirable to include free drug and combined drug-derivative particles ina particular formulation. In constrast to some prior art vehicles whichare not biodegradable, the derivatives will eventually break down and beremoved undergoing a reaction such as hydrolysis to reform the originaldrug.

More particularly, the prolonged action drug formulation of the presentinvention comprises a pharmacologically effective amount of a drug insolid form dispersed in or coated by at least one solid chemicalderivative of the drug which has minor pharmacological activity relativeto the drug, in a concentration which is sufficient to substantiallyprolong the time during which the drug is released and ispharmacologically active. The combination is preferably a substantiallyintimate and uniform mixture, for example obtained by physical admixturefollowed by compaction and comminution, or by coprecipitation from acommon solution, or the drug and derivative can be melted together toform a fused solid; in a preferred procedure, the derivative orderivatives are coated onto, or otherwise encapsulate, particles of thedrug. In this regard, one or more derivatives can be formed at thesurface of the drug particles by chemical reactions as hereinafterdescribed. The combination has particular usefulness when administeredsubcutaneously or intramuscularly.

The aqueous solubility (in pH 7 phosphate buffered solution) of thederivative should be less than 0.20 mg./ml., preferably less than 0.01mg./ml. Depending upon the particular derivative and parent drug, thedrug will generally constitute about 25-95 weight percent of thecombination.

The prior art has used a variety of terms to characterize long-actingformulations. While one could draw distinctions between phrases such as"sustained action", "controlled release", "delayed release" and thelike, as a practical matter, these terms can be used somewhatinterchangeably. In this specification, the term "prolonged action" willbe used to indicate all long-acting formulations, that is, formulationsthat have pharmacokinetic characteristics such that the formulationprovides an extended length of release time than is normally found forthe released drug itself.

DETAILED DESCRIPTION

It will be appreciated that the underlying concept of the presentinvention has applicability to a wide variety of drugs. In particular,one could utilize as the chemical derivative component an acylatedderivative of the following drugs that are amenable to chemcialmodification: steroids, neuroleptics, antileprotics, antimalarials,adrenergics, and antituberculars.

The present invention is exemplified with reference to the antileproticdrug diaminodiphenyl sulfone, commonly known as dapsone. This is thedrug of choice in the treatment of leprosy, having strongpharmacological activity against the bacillus Mycobacterium leprae.Typical dosage is 50-100 milligrams per day for a period of five yearsor longer. Because of the chronic nature of this disease, a variety ofderivative repository drugs have been proposed as substitutes fordapsone. These are described by Sinkula, supra, with optimum depotactivity obtained with the diacetyl derivative of dapsone, 4',4"'-sulfonylbisacetanilide, commonly known as acedapsone. Acedapsone isreported by Sinkula as having an aqueous solubility (pH 7 phosphatebuffered solution) of 0.003 mg./ml.

When used as a "prodrug", i.e., a compound which is biotransformed intoits pharmacologically active form, sufficient amount of the derivativemust be used to provide the required dosage amount of the parent drug.In accordance with the present invention, when acetylated derivativesare combining with dapsone, the derivatives serve not as a source of thedapsone but physically as a matrix or coating to control the release ofthe dapsone with which it is present in combination. In such context,the required amount of the diacetyl dapsone derivative (acedapsone) ismuch lower than when it is used as a prodrug. At the concentration usedin combination with dapsone, the acedapsone and monoacetyl dapsone haveminor pharmacological activity relative to the dapsone component.

Other suitable parent drug-derivative combinations can be provided. Forexample: the steroid drug testosterone can be coated or otherwisecombined with the derivative testosterone acetate; the neuroleptic drugfluphenazine can be coated with the derivative fluphenazine decanoate;the steroid drug hydrocortisone can be similarly coated with thederivative hydrocortisone propionate; the antimalarial drug cycloguanilcan be coated with the lauroyl derivative of cycloguanil; the adrenergicdrug dopamine can be coated with the decanoyl derivative of dopamine;and the antitubercular drug isoniazid can be combined with the lauroylderivative of isoniazid.

Further examples can be constructed by considering the aqueoussolubilities of various drug derivatives. In general, derivatives thatare more soluble than 0.20 mg./ml. show little depot activity andtherefore would be of little interest for the present combinations.Compounds of solubility below 0.20 mg./ml., preferably 0.01 mg./ml. orlower, are suitable candidates. Experimentally, one could determine thepharmacological activity of the derivative candidate and of the drug andcombinations thereof to generate a simple concentration relationship sothat a particular formulation can be customized.

The components may be intimately and uniformly dispersed which can beaccomplished by compaction of a simple admixture and comminution. As analternative to physical admixture, one can obtain a substantiallyintimate and uniform combination by coprecipitation of the drug with thederivative. For example, one can dissolve the drug and the derivative ina suitable solvent. The coprecipitate is prepared by either removing thesolvent in vacuo or adding a liquid miscible with the solvent but inwhich both drug and the derivative have only a low solubility.

Another method of combining the components is to melt the combination toform a fused solid upon cooling.

A preferred method is to chemically treat particles of the drug in sucha manner that the surface of each particle is converted to the desiredderivative(s), thereby coating each particle with the less solublederivative(s).

Acylated derivatives have been shown to be particularly useful in thisregard, and are formed through the use of acylating agents to formN-substituted amides or esters at appropriate locations on the parentdrug.

The combination can be used in accordance with any procedure in whichthe drug or prodrug has been used. For example, it can be suspended inaqueous solution or in oil, as appropriate, and injected as asuspension. Alternatively, the material can be implanted in the form ofa pellet or as a thin wafer, or injected as microcapsules. Because asubstantially smaller amount of the derivative is used in the presentcontext than as a prodrug, one can stay within reasonable bounds ofinjection volume, for example 2 ml or less for subcutaneous injectionand 5 ml or less for intramuscular injection.

The following examples will further illustrate the invention.

EXAMPLE I

One can combine 0.5 grams of diaminodiphenyl sulfone (dapsone) with 0.5grams of 4', 4"'-sulfonylbisacetanilide (acedapsone) by physicaladmixture using a mortar and pestle. The mixture is then compressed andbroken down to particles of a size than can be readily injected. Theresulting mixture is suspended in 3 ml of water for injection to serveas a subcutaneous or intramuscular injection. A person suffering fromleprosy is given an intramuscular injection of 3 ml (containing 1 gramof the combination), the injection being repeated only once per month.

EXAMPLE II

The procedure of Example I is repeated except that the combination isobtained by coprecipitation of the dapsone and acedapsone from commonsolution. In this regard, one can dissolve both dapsone and acedapsonein the minimum amount of the solvent dimethylformamide. A coprecipitateis formed on the addition of an excess of water, separated by filtrationand subsequently dried. The resultant combination is treated as inExample I.

EXAMPLE III

A combination is obtained by physically admixing in a mortar and pestle0.5 grams of dapsone and 0.5 grams of acedapsone. The combination iscompressed in a suitable punch and die assembly to a pellet weighing 1.0grams each. The pellets are then implanted subcutaneously, the woundbeing sutured for complete enclosure of the implant. Because of thebiodegradable nature of the component, no subsequent recovery of theimplant is required.

Following examples refer to coated particles having prolonged drugaction, prepared by reaction of the particle surface in situ. In generalterms, for surface conversion, particles of an appropriate diameter werereacted with an acylating agent (which can be as a pure liquid, presentin a solution with other materials, or as a vapor alone or diluted withother gases) for a period of time sufficient to cause the desired degreeof reaction at the particle surface.

EXAMPLE IV

A pellet of dapsone, formed by compressing particles at a pressure of4,000 pounds dissolved at the rate of 0.027 mg/cm² /min at 37° C. understandardized conditions. A second pellet formed in the same manner wasimmeresed in acetic anhydride for 10 minutes, and then warmed withwater. The dissolution rate of dapsone from the second pellet was foundto have fallen to 0.005 mg/cm² /min.

EXAMPLE V

One gram of dapsone particles lying within the range of 104 to 208microns were dispersed in acetic anhydride liquid at 24° C. After 1minute the suspension was filtered, the particles so collected beingwashed thoroughly with water and then dried. The particles were found tocontain approximately 70% of dapsone, the remainder being acetylatedforms of dapsone.

EXAMPLE VI

One gram of dapsone powder, with particle size lying in the range of 104to 208 microns was added to 35 ml of acetic anhydride in tolune (1:6parts v/v at 24° C. in a 125 ml glass stoppered flask. The suspensionwas stirred for 14 minutes at which time it was filtered. The particleswere washed several times with 10 ml portions of toluene and then airdried. Analysis showed the particles to contain 56% w/w dapsone, 27% w/wmono-acetylated dapsone and 17% w/w acedapsone. In other experimentsconducted at 10° C., the reacted particles were found to have acomposition of 83% w/w dapsone, 8% mono-acetylated dapsone and 9%acedapsone after being dispersed for 10 minutes in the 1:6 aceticanhydride/toluene solution.

EXAMPLE VII

Dapsone (0.5 gm) having a particle size within the range of 104 to 208microns was placed in a desiccator saturated with acetic anhydride vaporat 24° C. After 120 minutes, a sample was removed, analyzed and found tocontain 67.9 mole % dapsone, 7.0 mole % mono-acetylated dapsone, and25.1 mole % acedapsone. Using a standardized dissolution procedure at37° C., 33.4% of the dapsone was found to dissolve in 48 minutes,compared to 50.1% in the same time for unreacted dapsone of the samemean particle size.

EXAMPLE VIII

Dapsone (1.0 gm) having a particle size distribution in the range of 104to 125 microns was rotated at 25 rpm in a small wire mesh cylindersituated inside a 500 ml round bottomed flask containing aceticanhydride vapor at 24.5° C. for a period of 20 hours. At the end of theexperiment, the particles were found to contain 47.6% dapsone, 10.0%mono-acetylated dapsone and 42.4% acedapsone. Using a standardizeddissolution procedure at 37° C. it was found that 57.5% of the dapsonepresent dissolved in 128 minutes. For unreacted dapsone of a similarsize, an equivalent percentage dissolved in only 24 minutes. A sample ofthe reacted material was also subjected to dry heat at 110° C. for fourhours. It was found that the dissolution rate was essentially unchanged.

EXAMPLE IX

The reacted material of Example VIII, containing 47.6% dapsone, wasinjected intramuscularly into a dog at a dose level of 40 mg/kg. Asecond dog received a similar dose of unreacted dapsone of the sameparticle size. Under steady state conditions over a nine day period, itwas found that the serum level of dapsone arising from the surfacereacted material was 0.95±0.15 micrograms per ml, while that for thenon-reacted material was 2.75±0.49 micrograms per ml. On the basis ofequivalent amounts of dapsone present, the serum levels of dapsone fromthe surface reacted material averaged 73% of those obtained from puredapsone particles of the same size. Thus, the reduced dissolution ratesobserved in vitro were found to occur in vivo in the dog i.e., thematerial is being released from the muscle site more slowly than anequivalent dose of the unreacted (i.e., pure) dapsone of the sameparticle size.

It will be appreciated that the above listing of drugs and derivativesis not intended to be comprehensive, but merely representative of thewide variety of drugs and derivatives which can be used to constitute acombination of this invention. Those skilled in the art will know orwill be able to determine by routine experimentation the many otherspecific drugs and derivatives that are also suitable.

What is claimed is:
 1. A prolonged action drug formulated forintramuscular or subcutaneous administration, comprising incombination:a pharmacologically effective amount of a drug in solidparticulate form, said drug being selected from steroids, neuroleptics,antileprotics, antimalarials, andrenergics, and antituberculars; and asolid chemical derivative of said drug in the form of a coating onparticles of said drug obtained by acylation at the surface of said drugparticles, said derivative having an aqueous solubility of less than0.20 mg/ml in a concentration which is sufficient to substantiallyprolong the time during which said drug is pharmacologically active andhaving at said concentration minor pharmacological activity relative tosaid drug, said drug constituting about 25-95 weight percent of saidformulation.
 2. The formulation of claim 1 in which the aqueoussolubility of said derivative is less than 0.01 mg./ml.
 3. Theformulation of claim 1 or 2 wherein said derivative is a monoacetyland/or diacetyl derivative of said drug.
 4. A prolonged action drugformulated for intramuscular or subcutaneous administration, comprising,in combination:a pharmacologically effective amount of a drug in solidparticulate form, said drug being selected from testosterone,fluphenazine, hydrocortisone, cycloguanil, dopamine and isoniazid; and asolid chemical derivative of said drug in the form of a coating onparticles of said drug obtained by reaction at the surface of said drugparticles, said derivative having an aqueous solubility of less than0.20 mg/ml in a concentration which is sufficient to substantiallyprolong the time during which said drug is pharmacologically active andhaving at said concentration minor pharmacological activity relative tosaid drug, said drug constituting about 25-95 weight percent of saidformulation.
 5. In a method for the preparation of a drug in solidparticulate form, said drug being selected from steroids, neuroleptics,antileprotics, antimalarials, andrenergics, and antituberculars, theimprovement according to which said drug is placed in combination with asolid chemical derivative of said drug said derivative being in the formof a coating on particles of said drug obtained by acylation at thesurface of said drug, said derivative having an aqueous solubility ofless than 0.20 mg/ml whereby to provide a concentration sufficient toobtain a formulation in which the time during which said drug ispharmacologically active is substantially prolonged and having at saidconcentration minor pharmacological activity relative to said drug, saiddrug constituting about 25-95 weight percent of said formulation.
 6. Ina method for subcutaneously or intramuscularly administeringpharmacologically effective amounts of a drug in solid particulate formsaid drug being selected from steroids, neuroleptics, antileprotics,antimalarials, andrenergics, and antituberculars, the improvementaccording to which said drug is placed in combination with a solidchemical derivative of said drug, said derivative being in the form of acoating on particles of said drug obtained by acylation at the surfaceof said drug, said derivative having an aqueous solubility of less than0.20 mg/ml whereby to provide a concentration sufficient to obtain aformulation in which the time during which said drug ispharmacologically active is substantially prolonged and having at saidconcentration minor pharmacological activity relative to said drug, saiddrug constituting about 25-95 weight percent of said formulation.
 7. Theimprovement of claim 5 or 6 in which the aqueous solubility of saidderivative is less than 0.01 mg./ml.
 8. The improvement of claim 5 or 6in which said derivative is a monoacetyl and/or diacetyl of said drug.